Spinal muscular atrophy (SMA), one of the most widespread childhood genetic disorders in humans, is due to the loss of the telomeric SMN1 gene and partial rescue by the centromeric homolog SMN2 which is similar to SMN1 but that, due to splicing errors, makes very little functional SMN protein. Predominant symptoms include progressive failure of the neuro-muscular system, motor neuron loss, muscular weakness and atrophy. Therapeutic options are currently absent, and, therefore, their development requires aggressive investments in research to understand underlying disease mechanisms. Mouse models of SMA rely on deletion mutants that are supplemented with the human SMN2 gene, and also more recently tissue specific knock outs of SMN. Collectively, experiments using this model system have essentially supported a neuronal origin of SMA. In Drosophila, mutations in the single homolog of SMN display reduced viability, mobility defects and aberrations in the number of pre-synaptic contacts at the neuro-muscular junction (NMJ). Importantly, SMA phenotypes in flies seem to rely strongly on SMN function in muscle, and together with several reports from vertebrate models that highlight the insufficiency of a neuron-only model, suggest that the muscle is not a passive player in SMA pathophysiology. Indeed SMA can be viewed as a disease that arises from improper synaptic maintenance at the NMJ. A sub-optimal NMJ is likely to be defective in synaptic transmission, leading to abnormal motor behavior. However, a thorough electrophysiological evaluation of SMN mutations to understand the relative importance of reduced SMN in muscles has been lacking. Such analysis is now feasible due to the recent description of RNAi alleles that can be used to selectively knock down SMN in muscle tissue. Additionally, genetic screens have been conducted to identify genes that modify SMN dependent phenotypes in search of potential genetic elements that may be manipulated as therapy for SMA. One such candidate, the FGF pathway rescues structural defects at the synapse that arise from loss of SMN in muscles, though it is unclear whether electrophysiological defects in SMA will also be rescued by FGF. In this proposal, we address these outstanding questions by first examining electrophysiological and behavioral phenotypes that are caused by muscle specific loss of SMN in Drosophila. We next evaluate the efficacy of the FGF signaling pathway in rescuing these phenotypes. Thus, this project represents the first focused assessment of electrophysiological consequences that result from loss of SMN in the muscle tissue.